WO2018069409A1 - Lyophilized compositions comprising rhannexin v-128, process for their preparation and their use for preparing formulations containing 99mtc-rhannexin v-128 - Google Patents
Lyophilized compositions comprising rhannexin v-128, process for their preparation and their use for preparing formulations containing 99mtc-rhannexin v-128 Download PDFInfo
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- WO2018069409A1 WO2018069409A1 PCT/EP2017/075967 EP2017075967W WO2018069409A1 WO 2018069409 A1 WO2018069409 A1 WO 2018069409A1 EP 2017075967 W EP2017075967 W EP 2017075967W WO 2018069409 A1 WO2018069409 A1 WO 2018069409A1
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- rhannexin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/087—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being an annexin, e.g. annexin V
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- Lyophilized compositions comprising rhAnnexin V-128, process for their preparation and their use for preparing formulations containing 99m Tc-rhAnnexin V-128
- the present invention refers to labelled compounds in particular to Technetium labelled recombinant protein Annexin V-128.
- rhAnnexin - V- 128 is a known recombinant protein having sequence (SEQ ID N ° 1 ):
- This recombinant protein is described in Jin M. et al. "Essential Role of B-helix Calcium Binding Sites in Annexin V-Membrane Binding" The Journal of Biological Chemistry - Vol. 279 - No. 39 - pp. 40351-40357 (2004) and is a mutant form of Annexin V, a naturally occurring human serum protein, in which six amino acids (Ala- Gly-Gly-Cys-Gly-His) have been added to the N-terminus of rhAnnexin V (identical to wild type human Annexin V) to form an endogenous 99m Tc-binding site.
- cysteine in position 316 has been mutated to a serine (see the underlined S in the sequence above); with this mutation, the only cysteine remaining in the rhAnnexin V-128 sequence is the one in position 4, in the N-terminal 99m Tc-binding site.
- rhAnnexin V-128 is produced by known recombinant techniques in Escherichia coli (See for example Jin M. et al. "Essential Role of B-helix Calcium Binding Sites in Annexin V-Membrane Binding" The Journal of Biological Chemistry - Vol. 279 - No. 39 - pp. 40351 ⁇ 10357 (2004)) and it is stored in frozen form.
- the modification introduced in the N-terminus allows the binding of the protein with 99m Tc to form the corresponding labelled protein that, thanks to its mechanism of action, has a broad spectrum of potential applications both as a diagnostic tool, as well as for monitoring treatment efficacy and is normally used by intravenous administration.
- cardiovascular diseases in particular aortic aneurysm
- chemotherapy card iotoxi city and atherosclerosis can be considered.
- transplant rejection e.g., transplant rejection
- autoimmune diseases other than Rheumatoid Arthritis, e.g. Inflammatory Bowel Disease
- neurodegenerative diseases e.g., rheumatoid Arthritis, e.g. Inflammatory Bowel Disease
- transplant rejection e.g., transplant rejection
- autoimmune diseases other than Rheumatoid Arthritis, e.g. Inflammatory Bowel Disease
- neurodegenerative diseases e.g., neurodegenerative diseases.
- the cysteine present in the rhAnnexin V-128 can easily lead to dimerization due to the formation of a disulfide bridge between two cysteines, thus decreasing the chemical purity of the preparation.
- the protein is subjected to protein aggregation, a physical phenomenon in which misfolded proteins aggregate.
- rhAnnexin V-128 undergoes several stressful process steps (freeze-thawing, bulk formulation, lyophilization), as well as long-term storage and reconstitution with radioactive 99m TcO 4 - solution, during which aggregation is likely to occur. For these reasons the chemical purity is an analytical parameter which has to be carefully monitored in this preparation.
- the radiochemical purity is also a critical parameter for radiopharmaceuticals. It is essential both for safety reasons and also for its technical/diagnostic performance.
- the labeling with 99m TcO 4 - occurs through a series of reactions/equilibriums involving REDOX reactions and trans-chelation, and several radiochemical impurities may form if the conditions are not optimal.
- the recombinant protein rhAnnexin V-128 is sensitive, can flocculate during freeze-thawing, can dimerize through the free SH groups of the Cys, both during the thawing process, the manufacturing process and also during radiolabelling.
- a specific formulation is necessary for creating suitable conditions leading to a final 99m Tc-rhAnnexin V-128 preparation with high radiochemical and chemical purity, and high stability.
- Tait's work describes a two vials kit approach (with rhAnnexin V-128 in the form of a solution), that requires a final purification to obtain the 99m Tc-rhAnnexin V- 128.
- This is not an optimal formulation, as the final purification is an important drawback in routinely clinical practices because it requires a rather complex manipulation of the product, with associated radio safety and sterility issues and not compatible with pharmaceutical quality standards.
- the described method comprises mainly two steps: 1 ) preparation of a phosphate buffer solution (pH 7.4) containing the protein, glucoheptonate and EDTA as transitional ligands, Stannous salt and diluted hydrochloric acid; 2) 99mTc04 Na is added to the solution in step 1 and the so-obtained solution is mixed in water batch at 35-37 °C to give the labeled product 99mTc-Cys-Annexin V.
- a phosphate buffer solution pH 7.4
- 99mTc04 Na is added to the solution in step 1 and the so-obtained solution is mixed in water batch at 35-37 °C to give the labeled product 99mTc-Cys-Annexin V.
- the Annexin V according to CN 103159842 differs from the present Annexin V -128 since it presents a single Cysteine residue on the C-terminal, which is able to bind Tc-99m, while it lacks the modified N-terminus, with the addition of six amino acids (among which there is one Cys); moreover, in Annexin V -128 the Cys that was present in position 316 has been substituted by a Serine, thus subtracting a residue that favors dimerization via disulphide bonds.
- This labeling process should be based on direct reconstitution of a pre-formulated single vial possibly without requiring any additional filtration or purification step prior to injection.
- Figure 1 reports a schematic view of the process for the preparation of the lyophilized rhAnnexin V-128 according to the invention
- Figure 2 shows SPECT images of 99m Tc-rhAnnexin V-128 uptake in front paws of a healthy mouse (a) and in a mouse model of collagen induced arthritis (b).
- Figure 3c shows the uptake in the CIA mouse after treatment with an anti-inflammatory drug (no 99m Tc-rhAnnexin V-128 uptake detectable anymore).
- composition comprising lyophilized rhAnnexin V-128 suitable for the preparation of 99m Technetium formulation for intravenous administration.
- the present invention allows to overcome the above said problems thanks to a lyophilized composition suitable for intravenous administration comprising Annexin V- 128 in combination with suitable excipients, including particularly an antioxidant agent, in a pH range of 5.0 - 6.6.
- the present application refers also to a formulation obtained by adding to the above said composition a suitable volume of eluate from a commercial 99m Tc0 4 - generator.
- the lyophilized composition as above defined includes also a specific buffer.
- the antioxidant is included with the purpose of decreasing the Annexin V-128 dimer content both during the long-term storage of the lyophilized composition and also in the 99m Tc-rhAnnexin V-128 preparation after labeling. In the absence of the antioxidant the dimer formation was not under control, leading to a non-adequate chemical purity.
- antioxidant agent allowed to limit the dimer formation and ensure a dimer content below 10% during the long-term storage of the lyophilized composition and also for at least 6 h after radiolabeling.
- the antioxidant has a key role in maintain a good level of chemical purity and it is not added with the purpose of preventing the re-oxidation of reduced technetium to pertechnetate.
- Different antioxidants such as sodium metabisulfite, nicotinamide, pyridoxine hydrochloride, a- tocopherol acetate, monothioglycerol, were evaluated.
- citrate buffer initially the use of citrate buffer was attempted, as this is the buffer in which Annexin V-128 is currently stored. However, a radiochemical purity around 85-90% could only be achieved. With the purpose of shifting the radiochemical purity value above 90%, which is the commonly accepted lower limit for radiopharmaceutical preparations, different buffers, such as lactate, succinate, glycolic, TRIS and histidine, were evaluated. The lactate buffer was chosen, as it allowed to reach radiochemical purity values consistently around 94- 96%.
- the antioxidant and of the specific buffer allowed also to obtain a single- vial lyophilized composition with a long-term stability of at least 18 months.
- the lyophilized composition described in the previous art is declared to be stable for 210 days.
- the antioxidant and the specific buffer mentioned above are included in lyophilized composition comprising also:
- the composition can also include a radiation stability enhancer and/or a solubilizer.
- - buffer pH comprised between 5.0 and 6.6, with a concentration above 10 mM - reducing agent: above 0,005 mg/vial;
- the composition can also include a radiation stability enhancer in a quantity above 0,005 mg/vial and/or a solubilizer in a quantity above 1 mg/vial Several tests were performed during the development in order to define the above- described composition. Initially, the rhAnnexin V-128 lyophilized composition was prepared in presence of citrate buffer, including the following components:
- the rhAnnexin V-128 lyophilized composition was prepared in presence of lactate buffer, instead of citrate, at different pH values (up to 6.4), in the absence of antioxidant agent.
- lactate buffer instead of citrate
- pH increase favors dimer formation, the dimer percentage increasing more rapidly at higher pH, after radiolabeling.
- a third step the presence antioxidant agent and lactate buffer were tested.
- a lyophilized composition similar to the previous one was prepared, at a pH of 5.8, including also an antioxidant (sodium metabisulfite).
- an antioxidant sodium metabisulfite
- the radiochemical purity was confirmed to be well above 90% and the chemical purity was remarkably improved, giving values around 97-98% (by SEC-HPLC and RP- HPLC) for at least 6 h after radiolabeling.
- a lyophilized composition according to the present invention can be prepared according to a process comprising the following steps (see also Fig. 1 ):
- the final 99m Tc-rhAnnexin V-128 formulation suitable for intravenous administration can be prepared by adding to the above said composition a suitable volume of eluate from a commercial 99m Tc0 4 - generator containing up to 740 MBq of radioactivity and keeping the vial under slight rotation for 90 min at room temperature.
- composition/formulation according to the invention as well as of their process of preparation as above described are the use of an antioxidant agent and the use of a specific buffer, in the pH range 5.0 - 6.6.
- the lyophilized composition according to the invention has a shelf life of at least 18 months at 2-8 °C, and can be radiolabeled at room temperature, giving a high chemical and radiochemical purity and good stability for at least 6 hours after labeling, with a controlled dimer percentage.
- composition according to the invention makes the rhAnnexin V-128 available as a lyophilized single vial product that needs just to be reconstituted with a 99m Tc0 4 - solution eluted from a commercially available generator without the need for any final purification.
- the formulation according to the invention was tested for its diagnostic performance in several animal models (liver apoptosis, collagen induced arthritis model, endocarditis/myocarditis, inflammatory bowel disease, and others).
- Annexin V-128 was also tested for its toxicity in a complete preclinical toxicology package (designed in accordance with the relevant guidelines and with the input received from regulatory agencies), in 15 days repeated dose toxicology studies in rodent and non-rodent species. A cytokine release assay was also included in the preclinical package. The outcome of these studies showed that Annexin V-128 has a very favorable safety profile (data can be provided if needed).
- the formulation was tested for its safety and biodistribution in a Phase I study in human volunteers and is currently being tested in Phase II studies in Rheumatology and Cardiovascular indications.
- excipients were all dissolved in water for injection, in appropriate amounts: - D(+)-Trehalose dehydrate (powder): an appropriate amount was weighed to obtain a concentration of 50 mg/ml in the final bulk solution; - Sodium ⁇ -D-Glucoheptonate dihydrate (stock solution of 60 mg/ml): appropriate volume is added to obtain a concentration of 3 mg/ml in the final bulk solution;
- the final bulk solution was prepared adding an appropriate volume of rhAnnexin V- 128 solution to an appropriate volume of excipient bulk solution.
- the final bulk solution was filtered (0.22 ⁇ filter) and automatically filled into the vials (1 mL/vial) and lyophilized.
- the above said formulation can be used as a diagnostic tool and also for selecting the best treatment as well as for monitoring medical treatment efficacy in rheumatology (for example rheumatoid arthritis, Axial Spondyloarthritis), cardiovascular diseases (as for example aortic aneurysm, chemotherapy cardiotoxicity, endocarditis and myocarditis) atherosclerosis (in particular for the detection and staging of atherosclerotic plaque), oncology, transplant rejection, autoimmune diseases, neurology, and other pathologies having as a hallmark the process of apoptosis and/or as marker of treatment response for treatment-induced apoptosis.
- rheumatology for example rheumatoid arthritis, Axial Spondyloarthritis
- cardiovascular diseases as for example aortic aneurysm, chemotherapy cardiotoxicity, endocarditis and myocarditis
- atherosclerosis in particular for the detection and staging of atherosclerotic plaque
Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17794236.4A EP3541361A1 (en) | 2016-10-11 | 2017-10-11 | Lyophilized compositions comprising rhannexin v-128, process for their preparation and their use for preparing formulations containing 99mtc-rhannexin v-128 |
CN201780063039.XA CN110167528A (en) | 2016-10-11 | 2017-10-11 | Freeze-dried composition comprising rhAnnexin V-128, they preparation method and its be used to prepare containing99mThe purposes of the preparation of Tc-rhAnnexin V-128 |
US16/339,530 US20200038526A1 (en) | 2016-10-11 | 2017-10-11 | Lyophilized Compositions Comprising Rhannexin V-128, Process for Their Preparation and Their Use for Preparing Formulations Containing 99MTc-Rhannexin V-128 |
JP2019540703A JP2019533723A (en) | 2016-10-11 | 2017-10-11 | Lyophilized composition comprising rh annexin V-128, process for preparing the composition, and use of the composition for the preparation of a formulation comprising 99mTc-rh annexin V-128 |
US17/398,195 US20220031872A1 (en) | 2016-10-11 | 2021-08-10 | Lyophilized Compositions Comprising Rhannexin V-128, Process for Their Preparation and Their Use for Preparing Formulations Containing 99MTc-Rhannexin V-128 |
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Application Number | Priority Date | Filing Date | Title |
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IT102016000101875A IT201600101875A1 (en) | 2016-10-11 | 2016-10-11 | Lyophilized compositions comprising rhAnnexin V-128, process for their preparation and their use for the preparation of formulations containing 99mTc-rhAnnexin V-128 |
IT102016000101875 | 2016-10-11 |
Related Child Applications (2)
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US16/339,530 A-371-Of-International US20200038526A1 (en) | 2016-10-11 | 2017-10-11 | Lyophilized Compositions Comprising Rhannexin V-128, Process for Their Preparation and Their Use for Preparing Formulations Containing 99MTc-Rhannexin V-128 |
US17/398,195 Continuation US20220031872A1 (en) | 2016-10-11 | 2021-08-10 | Lyophilized Compositions Comprising Rhannexin V-128, Process for Their Preparation and Their Use for Preparing Formulations Containing 99MTc-Rhannexin V-128 |
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US (2) | US20200038526A1 (en) |
EP (1) | EP3541361A1 (en) |
JP (1) | JP2019533723A (en) |
CN (1) | CN110167528A (en) |
IT (1) | IT201600101875A1 (en) |
WO (1) | WO2018069409A1 (en) |
Citations (1)
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CN103159842A (en) | 2013-03-18 | 2013-06-19 | 江苏省原子医学研究所 | Cys-Annexin V kit used for 99mTc labeling and preparation method and application thereof |
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ATE190053T1 (en) * | 1994-05-19 | 2000-03-15 | Neorx Corp | AROMATIC AMINE-SUBSTITUTED LIGANDS WITH BRIDGED NITROGEN AND SULFUR DONORATOR ATOMS FOR IMAGE FORMING |
GB0427392D0 (en) * | 2004-12-15 | 2005-01-19 | Amersham Plc | Stabilised 99mTc compositions |
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2016
- 2016-10-11 IT IT102016000101875A patent/IT201600101875A1/en unknown
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2017
- 2017-10-11 WO PCT/EP2017/075967 patent/WO2018069409A1/en unknown
- 2017-10-11 JP JP2019540703A patent/JP2019533723A/en active Pending
- 2017-10-11 EP EP17794236.4A patent/EP3541361A1/en not_active Withdrawn
- 2017-10-11 US US16/339,530 patent/US20200038526A1/en not_active Abandoned
- 2017-10-11 CN CN201780063039.XA patent/CN110167528A/en active Pending
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CN103159842A (en) | 2013-03-18 | 2013-06-19 | 江苏省原子医学研究所 | Cys-Annexin V kit used for 99mTc labeling and preparation method and application thereof |
Non-Patent Citations (6)
Title |
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HARDY JONATHAN W ET AL: "[99mTc]Annexin V-128 SPECT Monitoring of Splenic and Disseminated Listeriosis in Mice: a Model of Imaging Sepsis", MOLECULAR IMAGING & BIOLOGY, ELSEVIER, BOSTON, vol. 17, no. 3, 22 November 2014 (2014-11-22), pages 345 - 354, XP035498291, ISSN: 1536-1632, [retrieved on 20141122], DOI: 10.1007/S11307-014-0804-6 * |
JIN M. ET AL.: "Essential Role of B-helix Calcium Binding Sites in Annexin V-Membrane Binding", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 279, no. 39, 2004, pages 40351 - 40357 |
LAHORTE C M M ET AL: "APOPTOSIS-DETECTING RADIOLIGANDS: CURRENT STATE OF THE ART AND FUTURE PERSPECTIVES", EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMA, SPRINGER VERLAG, HEIDELBERG, DE, vol. 31, no. 6, 1 June 2004 (2004-06-01), pages 887 - 919, XP008064142, ISSN: 1619-7070, DOI: 10.1007/S00259-004-1555-4 * |
LU C. ET AL.: "Kit formulation for 99mTc-labeling of recombinant Annexin V molecule with a C-terminally engineered cysteine", J RADIOANAL NUCL CHEM, vol. 304, 2015, pages 571 - 578, XP035920656, DOI: doi:10.1007/s10967-014-3859-6 |
TAIT ET AL.: "Structural Requirements for In Vivo Detection of Cell Death with Tc-Annexin V", THE JOURNAL OF NUCLEAR MEDICINE, vol. 46, no. 5, 2005, pages 807 - 815, XP002510935 |
TAIT JONATHAN F ET AL: "Structural requirements for in vivo detection of cell death with Tc-99m-annexin V", THE JOURNAL OF NUCLEAR MEDICINE, SOCIETY OF NUCLEAR MEDICINE, US, vol. 46, no. 5, 1 May 2005 (2005-05-01), pages 807 - 815, XP002510935, ISSN: 0161-5505 * |
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EP3541361A1 (en) | 2019-09-25 |
US20200038526A1 (en) | 2020-02-06 |
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JP2019533723A (en) | 2019-11-21 |
US20220031872A1 (en) | 2022-02-03 |
IT201600101875A1 (en) | 2018-04-11 |
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